Zithrox film-coated tablets 500 mg No. 3

Instructions for Zithrox film-coated tablets 500 mg No. 3

Composition

active ingredient: azithromycin;

1 tablet contains azithromycin dihydrate equivalent to azithromycin 250 mg or 500 mg;

Excipients: calcium hydrogen phosphate, pregelatinized starch, crospovidone, polysorbate 80, colloidal anhydrous silica, microcrystalline cellulose, sodium lauryl sulfate, talc, magnesium stearate, hypromellose, titanium dioxide (E 171), polyethylene glycol 400.

Dosage form

Film-coated tablets.

Main physicochemical properties:

250 mg tablets: white, biconvex, capsule-shaped, film-coated tablets, smooth on both sides;

500 mg tablets: white, biconvex, capsule-shaped, film-coated tablets with a breakline on one side and smooth on the other.

Pharmacotherapeutic group

Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. ATC code J01F A10.

Pharmacological properties

Pharmacodynamics.

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by the introduction of a nitrogen atom into the lactone ring of erythromycin A. The mechanism of action of azithromycin is to inhibit bacterial protein synthesis by binding to the 50 S subunit of ribosomes and inhibiting peptide translocation.

Mechanism of resistance.

Complete cross-resistance exists among Streptococcus pneumoniae, group A beta-hemolytic streptococcus, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.

The prevalence of acquired resistance may vary with location and time for the species concerned, so local information on resistance is necessary, especially in the treatment of severe infections. Qualified advice may be sought if the local prevalence of resistance is such that the efficacy of the drug in the treatment of at least some types of infections is questionable.

Spectrum of antimicrobial activity of azithromycin

*Methicillin-resistant Staphylococcus aureus has a very high prevalence of acquired resistance to macrolides and has been listed here because of its rare susceptibility to azithromycin.

Pharmacokinetics.

Bioavailability after oral administration is approximately 37%. Maximum serum concentration is reached 2-3 hours after administration.

When taken orally, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that the concentration of azithromycin in tissues is significantly higher (50 times) than in blood plasma, which indicates strong binding of the drug to tissues.

Serum protein binding varies with plasma concentrations and ranges from 12% at 0.5 μg/mL to 52% at 0.05 μg/mL in serum. The apparent volume of distribution at steady state (VVss) was 31.1 L/kg.

The terminal plasma half-life fully reflects the tissue half-life of 2-4 days.

Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in the urine over the next 3 days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also found in bile are 10 metabolites formed by N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses showed that the metabolites of azithromycin are not microbiologically active.

Indication

Infections caused by microorganisms sensitive to azithromycin:

ENT infections (bacterial pharyngitis/tonsillitis, sinusitis, otitis media);

respiratory tract infections (bacterial bronchitis, community-acquired pneumonia);

Skin and soft tissue infections: erythema migrans (initial stage of Lyme disease), erysipelas, impetigo, secondary pyodermatosis; acne vulgaris (common acne) of moderate severity;

sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindication

Hypersensitivity to azithromycin, erythromycin or any macrolide or ketolide antibiotic, or to any other component of the drug.

Interaction with other medicinal products and other types of interactions

Azithromycin should be administered with caution to patients taking other drugs that may prolong the QT interval.

Antacids: In a study of the effect of concomitant administration of antacids on the pharmacokinetics of azithromycin, there was generally no change in bioavailability, although peak plasma concentrations of azithromycin were decreased by approximately 25%. Azithromycin and antacids should not be taken concurrently.

Cetirizine: In healthy volunteers, coadministration of azithromycin with cetirizine 20 mg for 5 days at steady state did not result in any pharmacokinetic interaction or significant changes in the QT interval.

Didanosine: Coadministration of 1200 mg daily doses of azithromycin with 400 mg daily of didanosine in six HIV-positive volunteers had no effect on the steady-state pharmacokinetics of didanosine compared to placebo.

Digoxin and Colchicine: Concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin and colchicine has been reported to increase serum levels of the P-glycoprotein substrate. Therefore, the possibility of increased serum substrate concentrations should be considered when azithromycin is coadministered with a P-glycoprotein substrate such as digoxin.

Zidovudine. Single doses of 1000 mg and 1200 mg or multiple doses of 600 mg of azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these findings is unknown but may be useful for patients.

Azithromycin does not have a significant interaction with the hepatic cytochrome P450 system. It is believed that the drug does not have the pharmacokinetic drug interactions characteristic of erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 through the cytochrome-metabolite complex.

Ergot derivatives. Due to the theoretical possibility of ergotism, the simultaneous administration of azithromycin with ergot derivatives is not recommended.

Pharmacokinetic studies have been conducted on the use of azithromycin and the following drugs, the metabolism of which occurs to a large extent with the participation of cytochrome P450.

Atorvastatin: Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter plasma concentrations of atorvastatin (based on HMG-CoA reductase inhibition assay). However, postmarketing cases of rhabdomyolysis have been reported in patients receiving azithromycin with statins.

Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the plasma levels of carbamazepine or its active metabolites.

Cimetidine: In a pharmacokinetic study of the effect of a single dose of cimetidine taken 2 hours before azithromycin on the pharmacokinetics of azithromycin, no changes in the pharmacokinetics of azithromycin were observed.

Oral Coumarin Anticoagulants. In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. There have been reports of potentiation of the anticoagulant effect following concomitant administration of azithromycin and oral coumarin anticoagulants. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral coumarin anticoagulants.

Cyclosporine: A pharmacokinetic study in healthy volunteers given azithromycin 500 mg/day orally for 3 days followed by a single oral dose of cyclosporine 10 mg/kg demonstrated a significant increase in Cmax and AUC0-5 of cyclosporine. Therefore, caution should be exercised when these drugs are used concomitantly. If concomitant use of these drugs is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.

Efavirenz: Co-administration of a single dose of azithromycin 600 mg and efavirenz 400 mg daily for 7 days did not result in any clinically significant pharmacokinetic interaction.

Fluconazole: Coadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. The total exposure and half-life of azithromycin were not altered by coadministration of fluconazole, but a clinically insignificant decrease in maximum azithromycin concentration (18%) was observed.

Indinavir: Coadministration of a single dose of azithromycin 1200 mg had no statistically significant effect on the pharmacokinetics of indinavir, which was administered at a dose of 800 mg 3 times daily for 5 days.

Midazolam: In healthy volunteers, co-administration of azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam administered as a single 15 mg dose.

Nelfinavir. Co-administration of azithromycin (1200 mg) and nelfinavir at steady-state concentrations (750 mg 3 times a day) resulted in increased azithromycin concentrations. No clinically significant adverse events were observed, and no dose adjustment is required.

Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect the serum concentrations of these drugs. Neutropenia has been observed in patients receiving azithromycin and rifabutin concomitantly. Although neutropenia has been associated with rifabutin, a causal relationship to concomitant azithromycin has not been established.

Sildenafil: In healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite.

Terfenadine: No pharmacokinetic interaction has been reported between azithromycin and terfenadine. In some cases, the possibility of such an interaction cannot be completely excluded; however, there is no specific data on the existence of such an interaction.

Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are coadministered in healthy volunteers.

Triazolam: Coadministration of azithromycin 500 mg on the first day and 250 mg on the second day with 0.125 mg of triazolam in healthy volunteers had no significant effect on all pharmacokinetic parameters of triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole: Coadministration of double-strength trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin 1200 mg on day 7 had no significant effect on the peak concentrations, total exposure, or urinary excretion of trimethoprim or sulfamethoxazole. Serum azithromycin concentrations were consistent with those observed in other studies.

Application features

Allergic reactions: As with erythromycin and other macrolide antibiotics, rare serious allergic reactions have been reported, including angioedema and anaphylaxis (in isolated cases fatal), dermatological reactions including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome and toxic epidermal necrolysis (in isolated cases fatal). Drug reaction with eosinophilia and systemic symptoms (DRESS) has also been reported. Some of these reactions caused by azithromycin have resulted in recurrent symptoms and have required longer observation and treatment.

Hepatic impairment. Since the liver is the primary route of elimination for azithromycin, caution should be exercised when prescribing azithromycin to patients with severe liver disease. Cases of fulminant hepatitis, resulting in life-threatening liver dysfunction, have been reported with azithromycin. Some patients may have had a history of liver disease or were taking other hepatotoxic drugs.

Liver function tests should be performed if signs and symptoms of liver dysfunction develop, such as rapidly progressive asthenia accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy.

If liver function impairment is detected, azithromycin should be discontinued.

Ergot derivatives. In patients taking ergot derivatives, the simultaneous use of some macrolide antibiotics contributes to the rapid development of ergotism. There is no data on the possibility of interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin should not be prescribed simultaneously with ergot derivatives.

Superinfections: As with other antibiotics, observation for signs of superinfection due to nonsusceptible organisms, including fungi, is recommended.

Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including azithromycin, and has ranged in severity from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. C. difficile strains that hyperproduce toxins are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and require colectomy. The possibility of CDAD should be considered in all patients with antibiotic-associated diarrhea. Careful medical history is required, as CDAD has been reported to occur within 2 months of antibiotic therapy.

Prolongation of cardiac repolarization and QT interval, which increased the risk of cardiac arrhythmia and ventricular fibrillation (torsade de pointes), has been observed with other macrolide antibiotics, including azithromycin.

Since conditions associated with an increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be administered with caution to patients with pre-existing proarrhythmic conditions (especially women and the elderly), including patients with:

with congenital or registered prolongation of the QT interval;

who are currently being treated with other active substances known to prolong the QT interval, such as antiarrhythmics of classes IA (quinidine and procainamide) and III (dofetilide, amiodarone and sotalol), cisapride and terfenadine, neuroleptics such as pimozide; antidepressants such as citalopram, and fluoroquinolones such as moxifloxacin and levofloxacin;

with electrolyte imbalance, especially in the case of hypokalemia and hypomagnesemia;

with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure.

Myasthenia gravis: Exacerbation of symptoms of myasthenia gravis or new development of myasthenic syndrome have been reported in patients receiving azithromycin therapy.

Streptococcal infections. Penicillin is usually the drug of choice for the treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes, and is also used for prophylaxis in acute rheumatic fever. Azithromycin is generally effective in the treatment of streptococcal oropharyngeal infections; there are no data demonstrating the efficacy of azithromycin in the prevention of rheumatic fever. The safety and efficacy of intravenous azithromycin for the treatment of infections in children have not been established.

Other.

Safety and effectiveness for the prevention or treatment of Mycobacterium Avium Complex in children have not been established.

Use during pregnancy or breastfeeding

Pregnancy.

There are no adequate data on the use of azithromycin in pregnant women. In animal reproductive toxicity studies, azithromycin did not show teratogenic effects on the fetus, but the drug crossed the placenta. The safety of azithromycin during pregnancy has not been established. Therefore, azithromycin should be used during pregnancy only if the benefit outweighs the risk.

Breast-feeding.

Azithromycin has been reported to pass into human milk, but adequate and well-controlled clinical studies to characterize the pharmacokinetics of azithromycin excretion into human milk have not been conducted.

Fertility.

Fertility studies have been performed in rats; pregnancy rates were reduced following administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to influence reaction speed when driving vehicles or other mechanisms

There is no evidence that azithromycin can impair the ability to drive or use other mechanisms, but the possibility of developing adverse reactions such as delirium, hallucinations, dizziness, drowsiness, visual disturbances, fainting, and seizures, which may affect the ability to drive or use other mechanisms, should be taken into account.

Method of administration and doses

The drug must be taken 1 hour before or 2 hours after a meal, because simultaneous administration disrupts the absorption of azithromycin. Swallow the tablets without chewing. Take the drug once a day.

Adults and children weighing ≥ 45 kg.

For infections of the ENT organs, respiratory tract, skin and soft tissues (except chronic migratory erythema), the total dose of azithromycin is 1500 mg (500 mg 1 time per day). The duration of treatment is 3 days.

For acne vulgaris, the recommended total dose of azithromycin is 6 g, which should be taken as follows: 500 mg once daily for 3 days, followed by 500 mg once weekly for 9 weeks. The second week's dose should be taken 7 days after the first tablet, and the next 8 doses should be taken at 7-day intervals.

For erythema migrans, the total dose of azithromycin is 3 g, which should be taken according to the following scheme: 1 g on the first day, followed by 500 mg once a day for 5 days.

For sexually transmitted infections, the recommended dose of azithromycin is 1000 mg (2 tablets of 500 mg or 4 tablets of 250 mg) once.

Elderly patients.

There is no need to change the dosage in elderly people.

Since elderly patients may be at risk for cardiac conduction abnormalities, caution is recommended when using azithromycin due to the risk of cardiac arrhythmia and torsade de pointes.

Patients with renal impairment.

For patients with mild renal impairment (glomerular filtration rate

10-80 ml/min) the same dosage can be used as for patients with normal renal function. Azithromycin should be administered with caution to patients with severe renal impairment (glomerular filtration rate less than 10 ml/min).

Since azithromycin is metabolized in the liver and excreted in the bile, the drug should not be used in patients with severe hepatic impairment. Studies related to the treatment of such patients with azithromycin have not been conducted.

Children.

Zithromax should be used in children weighing ≥ 45 kg. For this group of children, the adult dose is recommended.

Overdose

Experience with the clinical use of azithromycin suggests that adverse reactions that develop when taking higher than recommended doses of the drug are similar to those observed with the use of usual therapeutic doses, namely: they may include diarrhea, nausea, vomiting, reversible hearing loss. In case of overdose, if necessary, administration of activated charcoal and carrying out general symptomatic and supportive treatment measures are recommended.

Side effects

Infections and infestations: candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory dysfunction, rhinitis, pseudomembranous colitis.

From the blood system: leukopenia, neutropenia, eosinophilia, thrombocytopenia, hemolytic anemia.

Immune system disorders: angioedema, hypersensitivity reactions, anaphylactic reaction.

Metabolic: anorexia.

On the part of the psyche: nervousness, insomnia, agitation, aggressiveness, restlessness, delirium, hallucinations.

From the nervous system: headache, dizziness, drowsiness, paresthesia, dysgeusia, fainting, convulsions, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis, hypoesthesia.

From the organs of vision: visual disturbances.

Hearing disorders: hearing impairment; vertigo; hearing impairment, including deafness and/or tinnitus.

Cardiovascular system: palpitations, ventricular flutter-fibrillation (torsade de pointes), arrhythmia, including ventricular tachycardia, prolongation of the QT interval on the ECG, hot flashes, arterial hypotension.

From the respiratory system: dyspnea, epistaxis.

On the part of the digestive tract: diarrhea, vomiting, abdominal pain, nausea, gastritis, constipation, flatulence, dyspepsia, dysphagia, bloating, dry mouth, belching, mouth ulcers, hypersecretion of saliva, pancreatitis, tongue discoloration.

Hepatobiliary system: liver dysfunction, cholestatic jaundice, hepatic failure (which rarely resulted in death), fulminant hepatitis, hepatic necrosis.

Skin: rash, itching, urticaria, dermatitis, dry skin, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis (AGEP).

Musculoskeletal system: osteoarthritis, myalgia, back pain, neck pain, arthralgia.

From the urinary system: dysuria, kidney pain, acute renal failure, interstitial nephritis.

From the reproductive system: uterine bleeding, testicular disorders.

General disorders: chest pain, edema, malaise, asthenia, fatigue, facial edema, hyperthermia, pain, peripheral edema.

Laboratory indicators: decreased lymphocyte count, increased eosinophil count, decreased blood bicarbonate level, increased basophil level, increased monocyte level, increased neutrophil level, increased aspartate aminotransferase (AST) level, increased alanine aminotransferase (ALT) level, increased bilirubin level in the blood, increased urea level in the blood, increased creatinine level in the blood, changes in blood potassium levels, increased alkaline phosphatase level, increased chloride level, increased glucose level, increased platelet level, decreased hematocrit level, increased bicarbonate level, abnormal sodium level.

Injury and poisoning: complications after the procedure.

Information on adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex is based on clinical trial data and post-marketing surveillance. These adverse reactions differ in type or frequency from those reported with the immediate-release and long-release formulations.

Metabolic: anorexia.

From the psyche: dizziness, headache, paresthesia, dysgeusia, hypoesthesia.

On the part of the organs of vision: visual impairment.

From the auditory system: deafness, hearing impairment, tinnitus.

Cardiovascular system: palpitations.

From the digestive tract: diarrhea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools.

From the hepatobiliary system: hepatitis.

Skin: rash, itching, Stevens-Johnson syndrome, photosensitivity.

Musculoskeletal system: arthralgia.

General disorders: fatigue, asthenia, malaise.

Expiration date

3 years.

Storage conditions

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging

250 mg tablets: 6 tablets per strip; each strip in a cardboard box;

500 mg tablets: 3 tablets per strip; each strip in a cardboard box.

Vacation category

According to the recipe.

Producer

MACLEODS PHARMACEUTICALS LIMITED.

Address

Village Theda, PO Lodhimaira, Tehsil Baddi, District Solan, Himachal Pradesh - 174101, India (Block No. 1).